Trial finds that spironolactone significantly reduced hospitalization for heart failure in heart failure patients with a preserved ejection fraction but failed to decrease the incidence of the trial’s primary composite outcome.
Patients with heart failure and a preserved ejection fraction treated with spironolactone (Aldactone) did not experience significantly reduced composite risk of death from cardiovascular causes, aborted cardiac arrest, and hospitalization to manage heart failure, a recent trial funded by the National Heart, Lung and Blood Institute found. However, they did experience a significantly reduced rate of hospitalization for heart failure alone.
Mineralocorticoid-receptor antagonists such as spironolactone have been shown to improve outcomes in patients with heart failure and a reduced left ventricular ejection fraction, but there is little evidence concerning treatment in patients with a preserved ejection fraction. The Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial analyzed the efficacy of spironolactone treatment in improving clinical outcomes among patients with symptomatic heart failure and a left ventricular ejection fraction of 45% or more. The results of the trial
were published in the April 10, 2014, issue of the New England Journal of Medicine
The study randomly assigned 3445 patients from 233 medical sites in 6 countries to receive a 15 mg to 45 mg daily dose of spironolactone or placebo. Patients included in the study had also experienced an elevated natriuretic peptide level within the previous 60 days or a hospital admission to manage heart failure within the last year. Patients were stratified at randomization based on whether they had been hospitalized or had an elevated natriuretic peptide level. The primary outcome was a composite of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure.
The results indicated that adding spironolactone to the existing treatment regimen did not significantly decrease the incidence of the primary composite outcome. After an average follow-up of 3.3 years, 18.6% of patients treated with spironolactone died from cardiovascular causes, experienced aborted cardiac arrest, or were hospitalized to manage heart failure, compared with 20.4% among placebo patients. When each outcome was analyzed separately, the groups differed significantly only for heart failure hospitalizations; 12.0% of patients treated with spironolactone were hospitalized for heart failure compared with 14.2% of placebo patients. In addition, rates of all-cause mortality, all-cause hospitalization, myocardial infarction, and stroke did not significantly differ between the treatment groups.
When patients were analyzed by whether they had been hospitalized or had experienced an elevated natriuretic peptide level before the study, treatment with spironolactone significantly reduced the rate of the primary outcome in patients in the elevated natriuretic peptide group, but not those in the previous hospitalization group. These results were unexpected, and led the researchers of the study to perform additional post hoc analyses. The results from these analyses indicate that event incidence varied widely based on region. Only 8.9% of placebo patients from Russia and Georgia (the country) experienced a primary outcome event, compared with 31.8% of placebo patients from the Americas. In addition, the overwhelming majority of patients from Russia and Georgia were in the previous hospitalization group.
“Possible factors in such geographic variation include differences in the clinical characteristics of the patient population in each region as well as differences in standards of care and methodologic expertise in the conduct of clinical trials,” the authors of an accompanying editorial
The trial findings also highlight “the importance of natriuretic peptide levels as a predictor of adverse outcomes in heart failure and their value as an inclusion and quality criterion in clinical trials, nowhere more so than in heart failure with a preserved ejection fraction,” the editorialists conclude.